Our laboratory is elucidating the nature of the immune response to murine tumors and establishing principles which may enhance our ability to immunize patients against known tumor antigens and induce tumor regression with cytokine therapy. We have used tumor-reactive cytotoxic T-lymphocyte lines to identify tumor-associated antigens from model murine tumors as well as human renal cancer. Plans for murine studies include developing new tumor models to investigate the mechanisms for interleukin-2-induced tumor regression and study the roles of T-cells and specific tumor antigens in those regressions. In parallel patient studies, we developed methodologies for identifying tumor-specific CTL from patients with renal cell cancer and successfully used these techniques to identify an RCC-associated T-cell antigen. Unmutated FGF-5 was recognized in an HLA-A3 restricted fashion by RCC TIL from a patient showing spontaneous tumor regression. FGF-5 was expressed in 60% of RCC lines and in some other breast and prostate cancer lines which also were immunolgically recognized when transduced with HLA-A3. We are trying to identify specific epitopes for FGF-5 for vaccine development. We have also generated other tumor-specific T-cell lines from this patient (which do not recognize FGF-5) as well as other patients who have shown significant immune-mediated tumor regressions. We are currently cloning these antigens using expression cloning techniques and CTL screening methods developed and refined in the Surgery Branch. Two planned extensions of this work are; 1) to develop vaccine approaches both for therapy as well as to drive new T-cell generation and antigen discovery and; 2) to begin new clinical efforts in the use of these T-cell reagents as therapeutic reagents.